| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Steroid-refractory acute Graft-versus-Host Disease (GvHD) |
| Steroid-refraktäre akute Graft-versus-Host Erkrankung (GvHD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Steroid-refractory acute Graft-versus-Host Disease (GvHD) |
| Steroid-refraktäre akute Graft-versus-Host Erkrankung (GvHD) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10018799 |
| E.1.2 | Term | GVHD |
| E.1.2 | System Organ Class | 100000004870 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate efficacy of Ruxolitinib/BAT as compared to BAT alone at day 28 after randomization. |
|
| E.2.2 | Secondary objectives of the trial |
Overall response rate (ORR:CR+PR) at day 14
Proportion of patients with durable response to treatment, persisting for at least 4 consecutive weeks within 8 weeks after randomization
Time to treatment response
Proportion of patients with treatment failure
Response duration
Overall survival (OS)
Event-free survival (EFS)
Non Relapse Mortality (NRM)
Failure-free survival (FFS)
Steroid tapering failure rate
Ruxolitinib discontinuation rate (≥ 4 weeks)
Discontinuation rate of steroid therapy for GvHD
Response rates (PR and CR) after cross over from BAT alone to BAT and Ruxolitinib
Cumulative steroid dose until day 56
Reduction of GvHD blood biomarker rate
Graft failure rates
Quality of life (EORTC QLQ-C30 and QLQ-HDC29)
Rates and severity of chronic GvHD over time
Duration of inpatient stay
Frequency of adverse events, engraftment, infections.
Frequency of CMV reactivation |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Acute skin, intestinal (histologically confirmed) or liver GvHD > grade 1 according to standard criteria
2. Age >=18 years
3. Failure of previous treatment, defined as presence of at least one of the following criteria:
3a. Treatment with prednisone/prednisolone/methylprednisolone in a dose of at least 2 mg/kg and lack of response after at least 7 days treatment
3b. Treatment with prednisone/prednisolone/methylprednisolone in a dose of at least 2 mg/kg and progression after at least 3 days of treatment
3c. Failure to taper the prednisone/prednisolone to 0.6 mg/kg/day or methylprednisolone dose to <0.5 mg/kg/day
4. Written informed consent
5. Ability to understand the nature of the study and the study related procedures and to comply with them |
|
| E.4 | Principal exclusion criteria |
1. Uncontrolled underlying disease
2. Active bleeding
3. Absence of clinical signs of acute GvHD
4. Diagnostic or distinctive clinical signs of chronic GvHD
5. Uncontrolled bacterial, viral or fungal infection
6. Absolute neutrophil count <0.5 x103/µl
7. Evidence of transplant-associated microangiopathy (TAM)
8. Any previous JAK2 inhibitor treatment prior to study enrolment, except Ruxolitinib given prior to the allogeneic stem cell transplantation
9. Known Hypersensitivity to Ruxolitinib or any of the excipients
10. Known positivity for HIV, Hepatitis B or Hepatitis C at the time of screening.
11. Female patients who are pregnant or breast feeding
12. Concomitant use of any other investigational drug within the last thirty days before the start of this study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall response rate (ORR) at day 28 is defined as proportion of patients in each arm demonstrat-ing PR or CR without requirement for additional systemic IST at day 28 after randomization, as compared to time of randomization (Visit 1, day 1). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| day 28 after randomization |
|
| E.5.2 | Secondary end point(s) |
Efficacy:
Overall response rate (ORR) at day 14 is defined as proportion of patients in each arm demonstrating PR or CR without requirement for additional systemic IST at day 14 after randomization.
Proportion of patients in each arm who achieve a CR or PR without requirement for additional systemic IST, persisting for at least 4 consecutive weeks within 8 weeks after randomization.
Time to response is defined as time from randomization to the date of first documentation PR or CR.
Death or relapse/progression of underlying hematologic disease without prior response will be considered to be a competing event. Comparison of treatment arms is conducted until day 28 only, as crossover to Ruxolitinib is offered to non-responders then.
Rate of patients with treatment failure until day 28 after randomization.
The duration of response is assessed for responders only by calculating the time from first response to the date of first observation of aGvHD relapse/progression or the date of additional IST for GvHD.
Onset of chronic GvHD or death without prior observation of aGvHD relapse or progression is considered to be a competing events, and observations where neither occurred are treated as censored observations.
OS is defined as time from randomization to the date of death from any cause.
EFS is defined as the time from randomization to the date of recurrence of underlying hematologic disease, graft failure or death due to any cause
NRM is defined as the time from randomization to the date of death not preceded by hematologic disease recurrence.
Hematologic disease recurrence / progression is considered to be a competing event.
FFS is defined as the time from randomization to recurrence of underlying hematologic disease, graft failure, non-relapse mortality (NRM) or addition of new systemic IST for GvHD.
Onset of cGvHD is considered as a competing event.
Rate of patients in whom failure to taper steroids below methylprednisolone dose of 0.5 mg/kg/day (or equivalent <0.6 mg/kg/day of predni-sone/prednisolone) was observed within 56 days after randomization OR addition of any new IST for GvHD due to failure to taper steroids below methylprednisolone dose of 0.5 mg/kg/day (or equivalent <0.6 mg/kg/day of prednisone/prednisolone)
Rate of patients discontinued Ruxolitinib treatment for at least 4 weeks.
Discontinuation rate of steroid therapy for at least 4 weeks.
Overall response rate (ORR) at day 14 in this group is defined as proportion of patients demonstrating PR or CR without requirement for additional systemic IST at day 14 after date of cross over from BAT alone to Ruxolitinib/BAT.
Overall response rate (ORR) at day 28 in this group is defined as proportion of patients demonstrating PR or CR without requirement for additional systemic IST at day 28 after date of cross over from BAT alone to Ruxolitinib/BAT.
Proportion of patients who achieve a CR or PR without requirement for additional systemic IST, persisting for at least 4 consecutive weeks within 8 weeks after the date of cross over from BAT only to Ruxolitinib/BAT.
Cumulative steroid dose until day 56 will be calculated.
Reduction of GvHD blood biomarkers (see section definitions) on day 8 randomization.
For the calculation of relapse incidence rates, time from randomization to the date of relapse diagnosis will be calculated.
Death without prior relapse will be considered as a competing event.
For the calculation of graft failure incidence rates, time from randomization to the date of graft failure diagnosis will be calculated.
Death without prior graft failure will be considered as a competing event.
EORTC QLQ-C30 and EORTC QLQ-C29.
Time from randomization to the start date of any chronic GvHD.
Hematologic relapse/progression and death without prior chronic GvHD will be considered as competing events.
Safety:
Type, frequency, severity and relationship of adverse events to investigational product, engraftment, infections.
Frequency of CMV reactivation.
Number of nights in hospital.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| different time points, e.g. 14 days, 4 weeks, day 56, continuing between randomisation and end of study (for more details see protocol flow chart) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| best available treatment according DGHO-Onkopedia guidelines (March 2018) |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 60 |
| E.8.9.1 | In the Member State concerned days | |
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